Patients having recurrent, relapsed, or refractory cancers, such refractory metastatic small cell lung cancer (SCLC), are typically faced with a poor prognosis and few therapeutic options. For example, there are no FDA approved therapies for patients with chemorefractory SCLC, defined as progressive disease during or within 3 months after first line therapy, and the only therapy approved for use in the United States for recurrent SCLC is topotecan, which has a response rate of only 2-6% (Schiller, J. H., et al., Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593—a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 10:2114-22, 2001; von Pawel, J., et al., Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17:658-67, 2007). Thus, there is a need for a diagnostic method to assess whether a patient having a cancer, and particularly a patient having recurrent, relapsed, or refractory cancer may derive a clinical benefit from a therapy.
Small molecule compounds, including ABT-737 and ABT-263, are inhibitors of the Bcl-2 family members Bcl-2, Bcl-XL, and Bcl-w, and have been shown to induce regression of solid tumors, Oltersdorf, T., “An inhibitor of Bcl-2 family proteins induces regression of solid tumours”, Nature, 435: 677-681, 2005. ABT-737 has been tested against a diverse panel of human cancer cell lines and has displayed selective potency against SCLC and lymphoma cell lines, Ibid. ABT-737's chemical structure is provided by Oltersdorf et al. at p. 679.
Because of the potential therapeutic use of inhibitors for Bcl-2 family members, companion diagnostic assays are needed that are able to identify or classify patients, particularly patients having a refractive or recurring cancer, in order to indicate which candidate will benefit from treatment using Bcl-2 family inhibitor therapy. Additionally, there is a clear need to support this therapy with diagnostic assays using biomarkers that would classify cancer patients as candidates for, and facilitate monitoring the efficacy of, Bcl-2 family inhibition therapy.